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H I Seifart

Publications and source records attributed to H I Seifart.

15 recordsLinked to original sources
PubMed1995

High-performance liquid chromatographic determination of isoniazid, acetylisoniazid and hydrazine in biological fluids.

The basic principle of derivatization of a hydrazide moiety with an aldehyde as applied in the method developed by Lacroix et al. [J. Chromatogr., 307 (1984) 137-144] for the quantitation of isoniazid and acetylisoniazid was improved by modification, standardization and extension to allow quantitation of hydrazine in patient samples. It could be shown that 40 microliters of 1% methanolic cinnamaldehyde per 200 microliters of deproteinized analysate gave maximal chromophoric isoniazid-cinnamaldehyde conjugate, read at 340 nm. The hydrolytic loss of isoniazid, crucial to the quantitation of acetylisoniazid, could be compensated for by introduction of an appropriate set of calibration curves. Although the method described here allows quantitation of monoacetylhydrazine and diacetylhydrazine, in addition to hydrazine, in mono-spiked samples, the method cannot be used for the quantitation of the acetylated metabolites of hydrazine in patient samples because of a lack of specificity. Linear calibration curves in the range 1-25 micrograms/ml for isoniazid and acetylisoniazid, 10-400 ng/ml for hydrazine and 50-1000 ng/ml for monoacetylhydrazine and diacetylhydrazine, could be constructed; analyte recoveries approaching 100% could be achieved in all instances.

Antitubercular Agents↗
PubMed1995

Isoniazid elimination kinetics in children with protein-energy malnutrition treated for tuberculous meningitis with a four-component antimicrobial regimen.

The impact of changing environmental factors--disease, nutrition and a high-dose multi-drug treatment regimen--on isoniazid (INH) elimination kinetics in children of both sexes and various ages was investigated. Thirteen children (mean age 2.3 years), hospitalized for the treatment of tuberculous meningitis, participated in the trial. Although all the children had protein-energy malnutrition, none had marasmus or kwashiorkor. After an oral dose of 20 mg/kg of INH, the concentrations in plasma were determined by the liquid chromatographic method of Lacroix et al. The 2-hour post-dose isoniazid concentration, the apparent first-order elimination rate constant and the corresponding INH half-life were determined in each child on two occasions 6 months apart. All comparisons were tested for significance using the Wilcoxon matched-pair signed-ranks test. There was no significant difference in any of the pharmacokinetic parameters of INH in our patients evaluated at the extremes of the 6-month term of treatment. It was apparent that changing conditions of disease and nutrition and a high-dosage, multi-component antimicrobial agent regimen over a 6-month period of treatment did not significantly influence INH elimination parameters. The trend evident in the pharmacokinetic profile of isoniazid in our children supports a trimodal distribution of acetylator phenotypes.

Anti-Bacterial Agents↗
PubMed1994

Hydrazine production in children receiving isoniazid for the treatment of tuberculous meningitis.

OBJECTIVE: To study the generation of the hepatotoxin hydrazine in 32 malnourished children receiving isoniazid for the treatment of tuberculous meningitis. DESIGN AND SETTING: This observational study was undertaken in the pediatric ward of a teaching hospital admitting children with advanced forms of tuberculous meningitis for treatment and management of complications. METHODS: Thirty-two children (mean age 2.28 years) receiving isoniazid 20 mg/kg/d were studied. Plasma isoniazid, acetylisoniazid, and hydrazine concentrations were determined by an HPLC method. Fourteen children were studied at weekly intervals for the first month of treatment and again after six months of therapy; 18 additional children were studied on one or more occasions during the first month of treatment only. RESULTS: The area under the curve for hydrazine two to five hours after the isoniazid dose correlated with the isoniazid elimination rate and with acetylisoniazid generation. Hydrazine production increased significantly during the first month of treatment, but decreased to approximate initial values at six months. No correlation was found between any clinical or biochemical indicator of liver dysfunction and hydrazine production. CONCLUSIONS: Hydrazine is formed in significant concentrations during the metabolism of isoniazid in young children. However, additional factors such as preexisting liver damage (e.g., from viral hepatitis) may be necessary for it to reach its toxic potential.

Child↗
PubMed1993

Therapeutic monitoring of antituberculosis drugs by direct in-line extraction on a high-performance liquid chromatography system.

A direct in-line pre-column extraction technique in which guanidinium and ammonium sulfate are used, followed by column switching, was employed to analyze serum, plasma and cerebrospinal fluid samples of patients treated for tuberculous meningitis. Resolution of a wide range of polar to non-polar xenobiotics was obtained on a C8 silica column by using a linear gradient from a binary system consisting of solvent A (0.05 M KH2PO4) and solvent B (acetonitrile-isopropanol, 4:1, v/v). Apart from the antituberculosis drugs (isoniazid, pyrazinamide, ethionamide and rifampicin) the patients received up to sixteen different medicines for prevention of complications and the treatment of symptoms. Qualitative resolution of all the drugs was obtained by the chromatographic system. Quantitation of pyrazinamide and ethionamide was achieved with high precision and low inter-sample variation.

Antitubercular Agents↗
PubMed1992

Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients.

An HPLC method is described for measurement of plasma hydrazine (Hz) concentrations (CHz) at the same time as isoniazid (INH) levels (CINH). Study has been made of CHz during 2-5 after dose in healthy adults (A, n = 34), in adult pulmonary TB patients (B, n = 18) and in paediatric tuberculous meningitis patients (C, n = 25). Although the population has about equal proportions of 'slow' (52%) and 'fast' acetylators, in none of the groups could a correlation be shown between CHz levels or rates of Hz accumulation and any measure of acetylator type. Consequently Hz must be derived both from INH and from its metabolites during the first hours post-dose. For group A and ca. 70% of groups B and C a constant and maximal fraction of dose (ca. 0.6% for adults and 0.4% for paediatric patients) appeared as Hz at 4-5 h. For group B patients small pre-dose concentrations increased with duration of treatment. Four patients in group B showed the highest levels of CHz and rates of Hz accumulation some three times greater than the rest; all four had been identified as alcoholics and one showed evidence of hepatotoxicity at CHz (5 h) = 1.3% of dose. Amongst group C (9/25) episodes of high CHz greater than 0.5% of dose occurred during the first weeks of treatment and one developed CHz ca. 100 ng/ml = 1.3% of dose coincidentally with indications of hepatic damage.

Acetylation↗
PubMed1992

Cerebrospinal fluid isoniazid concentrations in children with tuberculous meningitis: the influence of dosage and acetylation status.

Cerebrospinal fluid (CSF) and plasma isoniazid (INH) concentrations were determined on 96 occasions in 38 children (median age 1.5 years) with tuberculous meningitis, and the effects of INH elimination status and test dosages of 10 mg/kg body weight and 20 mg/kg body weight was studied. Maximum cerebrospinal fluid INH concentrations were reached during the period 2 to 4 hours after dosing and cerebrospinal fluid and plasma INH concentrations did not differ significantly during this period. Cerebrospinal fluid INH concentrations following a dosage of 10 mg/kg (4.6 +/- 2.4 micrograms/mL) were, however, significantly lower than those following a dosage of 20 mg/kg (11.6 +/- 2.7 micrograms/mL). Cerebrospinal fluid INH concentrations in faster acetylators at a dosage of 10 mg/kg (3.2 +/- 1.1 micrograms/mL) were significantly lower than in slower acetylators (7.7 +/- 1.3 micrograms/mL), as was the case with a dosage of 20 mg/kg, where faster acetylators had cerebrospinal fluid INH concentrations of 10.5 +/- 2.5 micrograms/mL compared with 14.1 +/- 1.4 microgram/mL in slower acetylators. Following dosages of both 10 mg/kg and 20 mg/kg, INH concentrations in excess of the minimal inhibitory concentration for Mycobacterium tuberculosis persisted in the CSF 12 to 14 hours later. Despite the patients' being young and frequently malnourished, suffering from advanced forms of tuberculous meningitis, and receiving high dosages of INH, rifampicin, and pyrazinamide, none developed any clinical signs of hepatotoxicity and in only one child did the serum bilirubin level rise to 19 micrograms/mL.

Acetylation↗
PubMed1991

Stability of isoniazid, rifampin and pyrazinamide in suspensions used for the treatment of tuberculosis in children.

The stability of monosuspensions, cosuspensions and multisuspensions of isoniazid (INH), pyrazinamide (PZA) and rifampin (RIF) has been evaluated by high pressure liquid chromatography over a period of 28 days both with and without the addition of vitamin C (20 micrograms/ml) and at ambient temperatures of 4 degrees C, 24 degrees C and 40 degrees C. At the end of 28 days greater than 90% of initial concentrations of INH, PZA and RIF in monosuspensions remained unchanged irrespective of ambient temperature as was the case with INH and PZA in cosuspension. The addition of RIF to either INH or PZA in cosuspension or together in multisuspension led to a marked fall in the concentration of one or more of the agents, an effect that was accentuated by the addition of vitamin C. In the case of a multisuspension of INH + RIF + PZA with vitamin C added, 41.7% (4 degrees C), 24.1% (24 degrees C) and 20.3% (40 degrees C) of initial INH concentrations and 1.9% (4 degrees C), 1.3% (24 degrees C) and 0.0% (40 degrees C) of initial RIF concentrations remained detectable after 28 days. The addition of vitamin C to monosuspensions of INH and PZA led to a marked decline in the amount of drug detectable and only in the case of RIF was greater than 90% of initial concentrations of the drug detectable after 28 days. The dispensing of cosuspensions or multisuspensions of antituberculosis agents containing RIF is inadvisable as is the addition of vitamin C in any form.

Ascorbic Acid↗
PubMed1990

Serum gentamicin assay: an assessment of two different Syva EMIT and Abbot TDx instruments.

The accuracy and reproducibility of two different Syva EMIT and Abbot TDx instruments for the determination of gentamicin were assessed. A series of spiked standard serum samples containing gentamicin in concentrations ranging from 0.88-17.82 mg/l were used for this purpose. Both TDx systems evaluated had excellent reproducibility but overestimated gentamicin levels in the clinically important concentration range in an apparent concentration-dependent way by at least 5 and 10%, respectively. In addition both these systems exhibited considerable carryover effects when high concentration gentamicin samples (17.82 mg/l) were alternated with serum blanks. Average gentamicin levels determined by the EMIT systems were much closer to the target values, especially those of EMIT-A, than those measured by the TDx-systems. The reproducibility, as measured by the coefficient of variation (CV), of the semi-automated EMIT systems over the entire concentration range investigated was about half that of the TDx-systems. No carryover effects were observed with the two EMIT-systems. This study has shown that the accuracy and reproducibility of both assay methods vary considerably over the clinically important gentamicin concentration range. In addition there may be a large variation between instruments of the same system especially in the critical trough region for gentamicin.

Fluorescence Polarization↗
PubMed1989

In vitro evaluation of ampicillin-gentamicin interactions.

Ampicillin at a concentration of 100 micrograms/mL was combined in vitro with either gentamicin 10 micrograms/mL in serum, 0.01 mol/L phosphate-buffered saline at 37 degrees C, or water at room temperature (25 degrees C). At these concentrations, which represent the peak prophylactic serum concentrations likely to be achieved by a 70-kg person after parenteral administration of 1.5 mg/kg gentamicin and 2 g of ampicillin, no clinically significant inactivating effects of these antibiotics on each other were observed over a period of six hours.

Ampicillin↗
PubMed1989

Cerebrospinal fluid concentrations of ethionamide in children with tuberculous meningitis.

Cerebrospinal fluid ethionamide concentrations were determined in 18 children (median age 26.5 months) with tuberculous meningitis complicated by raised intracranial pressure. Lumbar spinal fluid specimens were obtained before and after weekly hour-long monitoring of intracranial pressure. Thirty-five paired and four single specimens were evaluated. A dosage schedule of 15 mg/kg was used on 26 occasions, and a spinal fluid ethionamide concentration of 2.5 micrograms/ml, the in vitro minimal inhibitory concentration for Mycobacterium tuberculosis, was exceeded on only seven occasions (27%). A dosage of 20 mg/kg was administered on 13 occasions, and in only two instances (15%) was a concentration of 2.5 micrograms/ml not achieved. Ethionamide in a single daily dosage of 20 mg/kg should be considered for the initial treatment of tuberculous meningitis when the presence of isoniazid-resistant M. tuberculosis cannot be excluded.

Child, Preschool↗
PubMed1984

Endogenous immunoreactive digitalis-like substance in neonatal serum and placental extracts.

Therapeutic levels of digoxin in the serum of untreated neonates delivered to mothers who had not received the drug prenatally were detected by radio-immunoassay. Digoxin levels in neonates should be interpreted with care because of the unknown contribution by the endogenous digitalis-like substance (DLS) to the level of the drug. Three commercially available radio-immunoassay kits were compared with regard to their sensitivity and reproducibility in detecting the endogenous DLS. The kit from Clinical Assays (Cambridge, Mass., USA) was selected for further investigations. In a series of 35 paired samples of maternal and cord blood the average DLS values in terms of digoxin were 0,52 +/- 0,07 and 0,81 +/- 0,27 ng/ml respectively. This difference is statistically highly significant. In the case of infants with DLS values of 1-1,5 ng/ml in terms of digoxin, approximately 1 week was required to reach nontherapeutic digoxin levels, i.e. below 0,5 ng/ml. Gel chromatography showed that the DLS in neonatal serum was more closely associated with protein than is authentic digoxin. In placental extracts it followed the elution profile of the protein completely, but it shifted to fractions with a lower molecular weight than haemoglobin after trypsinization. The level of DLS in neonatal serum was also increased by more than half its original value by trypsinization. Proteolysis therefore seems to have a releasing effect on DLS. The molecular size of this substance is probably in the same range as that of polypeptides, since it was not dialysable from trypsinized and untreated samples through a membrane with a 22 000 dalton molecular weight cut-off point.

Adult↗
PubMed1980

Anoxic energy production and contractile activity in mammalian cardiac muscle.

Contractile activity of electrically driven left atria of guinea pigs was measured auxotonically under normoxic and anoxic conditions at various frequencies and temperatures in Krebs-Henseleit solution containing 15 mM glucose. At 35 degrees C, a frequency of 0.5 Hz and anoxia ("anoxia test") reduced contractile activity was observed, lasting 6.6 +/- 1.55 hr. Under normoxic conditions at 0.5 Hz and 35 degrees C the contractile work per beat (cwb) amounts to 35% of the maximum reached at 1.5 Hz, according to the force-frequency relationship. The total contractile work per hr only comes up to 5% of the maximum reached at 4.0 Hz. The oxygen consumption at 0.5 Hz only exceeds the value of resting atria by 10%. A positive inotropic peak of short duration observed directly after acute anoxia can be antagonized by beta-receptor blockade. Then contractile activity decreases during the first half hr of anoxia to around 20%-30% of the initial value under oxygen. In the second phase, the reduced contractile activity recovers and is stabilized at a level between 50%-80% of the control value during the first and second hour of anoxia and then decreases slowly during the following hours. The recovery period of anoxic contractile activity coincides with the time-dependent increase of the lactic acid production rate which reaches a maximum after around 1 hr of anoxia. This can also explain why the rapid decrease of ATP (30%) and creatine phosphate (CP) (90%) during the first 20 min is stabilized at this reduced value during the 2 hr of anoxia studied. Related to the measured oxygen consumption during normoxia, the glucose consumption increases during anoxia in resting atria approximately 300% and, in beating atria, approximately 650%, representing an ATP production rate of approximately 20% and approximately 50%, respectively, related to aerobic conditions. G-strophanthin enhances anoxic contractile activity up to 200% of the aerobic initial control value and prolongs the anoxic tolerance from 6.6 +/- 1.55 to 21.2 +/- 3.3 hr without significant additional increase of glycolysis or a further decrease of energy-rich phosphates. Addition of adenine and ribose as precursors of the adenine nucleotide pool during the first and second hours of anoxia increases anoxic contractile activity and avoids loss of ATP, ADP, and CP, without enhancemnt of glycolysis. The importance of these findings for anoxic survival of cardiac tissue is discussed. This "anoxia test" can be used to check influence on: 1) force and duration of anoxic contractile activity as well as anoxic arrhythmias (anoxic energy consumption), 2) the rate of anaerobic glycolysis (anoxic energy production), and 3) the concentration of energy-rich phosphates (energy storage).

Animals↗
PubMedDate not supplied

The influence of various precursors on the concentration of energy-rich phosphates and pyridine nucleotides in cardiac tissue and its possible meaning for anoxic survival.

A special "anoxia test" was developed with isolated guinea pig atria to test influences on the anoxic energy balance. Adenine, ribose, nicotinic acid or nicotinamide added as precursors to nutrition solutions inhibit the loss of cardiac adenine and pyridine nucleotides during anoxia and improve the energy balance under aerobic and anaerobic conditions in the myocardium.

Adenine↗